Abstract

Purpose: To investigate the prognostic relevance of Ki-67 labeling index (LI) in patients with Ductal Intraepithelial Neoplasia (DIN) of the breast.

Patients and Methods: From January 1997 to December 2007, histological samples and clinical data of 1,171 consecutive patients operated for DIN in a single institution were collected. The study was performed in accordance with the REMARK criteria. The independent prognostic role of Ki-67 LI was evaluated with a multivariable Cox regression model. A restricted cubic splines model was used to evaluate the prognostic role of Ki-67 LI as a continuous variable.

Results: Overall, median age was 52 years (range 23–88), median Ki-67 LI 15% (range 1–80) and median follow-up 86 months (range 1–192). Overall, 549 (46.9%) women were premenopausal at the time of diagnosis. A total of 872 (74.5%) patients underwent breast conservative surgery (BCS). Whole breast radiotherapy (RT) was administered to 356 patients, and 506 patients received low dose tamoxifen (HT) (20mg/week or 5 mg/day). Histologically, most of the cases had a prevalent solid or cribriform pattern (75%), were DIN1c and DIN2 (80%), ER+ (80%), and showed a high (≥14%) Ki-67 LI (54%). The prevalence of the immunohistochemically defined subtypes was 39.5% for Luminal (Lum) A, 22.8% for LumB/Her-2−, 18.2% for LumB/Her2+, 15.8% for Her-2+, and 3.7% for Triple Negative. Overall, the rate of invasive and in situ recurrences (5-year cumulative incidence) was 10.7%. Firstly, we analyzed the role of RT according to Ki-67 LI as a continuous variable in DIN2/DIN3 patients after BCS. The curve and interaction model was adjusted for menopause, BMI, Her-2 and ER status, histological grade, presence of necrosis and microcalcifications, and HT. RT was protective in subjects with DIN with Ki-67 LI ≥14%, while no evidence of effect was seen for Ki-67 LI <14%. Notably, the higher the Ki-67 LI, the stronger the effect of RT (P-value for the interaction between RT and Ki-67 LI <0.01). Accordingly, RT was effective in all DIN subtypes with the exception of LumA. The adjusted HRRT vs No RT for LumB/Her2−, LumB/Her2+, and Her2 subtypes was 0.20 (95 % CI, 0.08–0.48), 0.44 (95 % CI, 0.16–1.20), and 0.15 (95 % CI, 0.04–0.50), respectively. The HRRT vs No RT for Triple Negative subtype was 0.40 (95 % CI, 0.07–2.41) and was not adjusted because of the sparse number of events. Finally, we focused the analysis on DIN2 patients stratified by Ki-67 LI. Again, after adjustment for menopause, surgical margins, presence of necrosis, microcalcifications, and HT, RT was not effective in DIN2 patients with Ki-67 LI <14% [HRRT vs No RT: 1.15 (95 % CI 0.47–2.80)]. On the contrary, DIN2 patients with a Ki-67 LI ≥14% mostly benefit of RT in terms of ipsilateral recurrence[HRRT vs No RT: 0.18 (95% CI 0.07–0.46)]. Low dose tamoxifen was effective in either LumA [adjusted HRHT vs No HT: 0.56 (95 % CI 0.33–0.97)] and LumB/HER2− DIN [HRHT vs No HT: 0.51 (95 % CI 0.27–0.95)], but not in LumB/Her2+ [HRHT vs No HT: 1.06 (95 % CI 0.56–2.05).

Conclusion: Our data suggest that Ki-67 LI may be a useful prognostic and predictive adjunct in DIN patients.